Targeting Astrocyte Endothelin Axis for Therapy of Experimental Breast and Lung Cancer Brain Metastasis

Brain metastasis is associated fatal outcome. The median survival of patients with brain metastasis is 2 to 4 months. Radiotherapy and chemotherapy can increase the overall survival to 6 months. Development of novel therapeutic approaches to improve clinical outcomes is urgently needed.

Recently, we discovered that brain endothelial cells and astrocytes protect breast cancer cells and lung cancer cells from paclitaxel through an endothelin-dependent signaling mechanism that leads to the upregulation of anti-apoptotic proteins in cancer cells. The chemoprotective effect can be abolished by combined antagonism of ET_AR and ET_BR signaling or by siRNA targeting of both endothelin receptors on cancer cells. In this study, we determined the extent that endothelin signaling is critical for the survival of experimental breast and lung cancer brain metastases. Nude mice bearing established MDA-MB-231 breast cancer or PC-14 non-small cell lung cancer brain metastases were treated with vehicle, a dual endothelin receptor antagonist, macitentan, paclitaxel, or macitentan plus paclitaxel. Cell division, apoptosis, tumor vasculature, and expression of survival-related proteins were assessed by immunofluorescent microscopy.

Cancer cells and tumor-associated endothelial cells expressed activated forms of AKT and MAPK in vehicle- and paclitaxel-treated groups, but these proteins were downregulated in metastases of mice that received macitentan. The survival-related proteins BCL2L1, GSTA5, and TWIST1 in cancer cells and tumor-associated endothelial cells were suppressed by macitentan. Macitentan combined with paclitaxel produced a significant reduction in cancer cell division and marked apoptosis of both cancer cells and tumor-associated endothelial cells and produced complete responses in 35/35 mice. In conclusion, dual antagonism of ET_AR and ET_BR signaling sensitizes brain metastases to paclitaxel and may represent a new therapeutic option for patients with brain metastases.